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The first remarkably successful attempts to identify the active biochemicals found in antibacterial molds
followed the discovery of penicillin antibiotics by Fleming, identification of the structure by Hodgkin,
and synthesis by Chain, Heatley, and Florey, led to commercial preparation of penicillin. Subsequently,
many other families of β-lactam antibiotics have been developed and their extensive use worldwide
continues to be a forefront line of action against infectious pathogens.
Since many β-lactams have been widely accepted as safe and effective antibacterial drugs for more than
60 years, our hypothesis is that novel agents can be synthesized and selected within this class that will
have both an enhanced anticancer activity and low toxicity to normal tissues. Toward the goal, synthesis
of structurally diverse racemic and optically active new β-lactams derived from polycyclic imines has
been achieved following cycloaddition reaction. Diasteroselectivity and enantioselectivity of this reaction
has been investigated and unprecedented stereoselectivity has been realized. In vitro cytotoxicity and in
vivo study have been performed using US NCI protocol. The anticancer activity has exceeded than that of
clinically active cisplatin and other available anticancer drugs widely prescribed for chemotherapy.
Selective differences in cytotoxicity have also been evident in ovary, breast, liver, colon, pancreas,
prostate, skin and blood cancer cell lines. Notably, this exploration has identified highly active new β-
lactams that have also demonstrated remarkable activity against resistant cancer cell lines through specific
gene activation. Ames assay, topoisomerase inhibition and cell cycles have been investigated. The lead β-
lactams have demonstrated a blockade at the G2/M checkpoint in cancer cell lines and inhibited protein
synthesis, but they have no effects on topoisomerase enzymes. Studies have confirmed non-mutagenicity
of the most active compounds.
Chemical manipulation of the functionalized β-lactams has also been performed for the stereocontrolled
asymmetric synthesis of multicyclic heterocycles that are important protein kinase inhibitors, extremely
useful targets in cancer chemotherapy.
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